(1) We are evaluating an alternative gene therapy method using a new methodology, RNA/DNA hybrids, targeting cultured cells as well as utilizing the hybrids to create animal models of disease. The RNA and DNA portions have different functions, RNA targets the hybrid to a specific region in the genome, the DNA portion is thought to then induce a repair process to modify a single targeted base, resulting in the desired change within the genome. The method has been used to induce targeted single base genomic changes in cultured cells for three targets apolipoprotein B, hemoglobin and alkaline phosphatase. (2) Peptide nucleic acid (PNA) oligonucleotides have a higher affinity for native DNA than normal DNA oligonucleotides. PNA~s hybridization to DNA is also are more significantly destabilized by a single base mismatch. Utilizing these attributes, we have developed a PCR method to screen for rare single base mutations that constitute as little as 0.25% of the total sequences. Using a PNA that blocks PCR amplification of the normal sequence, the rare sequence is preferentially amplified. (3) We are investigating various gene therapy vector delivery systems in collaboration with Dr. Nancy Templeton Smyth at the NCI. She has developed methods that are reportedly up to 100 times more potent than traditional cationic liposome methods. We are evaluating these methods in the delivery of gene therapy vectors, RNA/DNA hybrids and antisense oligonucleotides to hepatocytes. 4) We have been evaluating the effect of niacin, a lipid lowering drug, on the markedly atherogenic lipoprotein Lp(a) in patients with systemic lupus erythematosus (SLE); another study is evaluating thyroid hormone induced changes in Lp(a) in thyroid cancer patients. During treatment for thyroid cancer, thyroid hormone levels are iatrogenically varied, allowing the effect of high and low levels of thyroid hormone on Lp(a) to be determined. We have been evaluating the effect of niacin, another lipid lowering drug, on the markedly atherogenic lipoprotein Lp(a). A collaborative study involves determining lipid effects of IL-6 was done in normal individuals. A single dose of IL-6 reduced cholesterol, trigylcerides and apolipoprotein B, while Lp(a) did not change.